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Low molecular weight protein tyrosine phosphatase (LMWPTP) upregulation mediates malignant potential in colorectal cancer.

Hoekstra E, Kodach LL, Das AM, Ruela-de-Sousa RR, Ferreira CV, Hardwick JC, van der Woude CJ, Peppelenbosch MP, Ten Hagen TL, Fuhler GM - Oncotarget (2015)

Bottom Line: In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia.Chemical inhibition of LMWPTP significantly reduces CRC growth.In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's Gravendijkwa, Rotterdam, The Netherlands.

ABSTRACT
Phosphatases have long been regarded as tumor suppressors, however there is emerging evidence for a tumor initiating role for some phosphatases in several forms of cancer. Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP; acid phosphatase 1 [ACP1]) is an 18 kDa enzyme that influences the phosphorylation of signaling pathway mediators involved in cancer and is thus postulated to be a tumor-promoting enzyme, but neither unequivocal clinical evidence nor convincing mechanistic actions for a role of LMWPTP have been identified. In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia. Chemical inhibition of LMWPTP significantly reduces CRC growth. Furthermore, downregulation of LMWPTP in CRC leads to a reduced migration ability in both 2D- and 3D-migration assays, and sensitizes tumor cells to the chemotherapeutic agent 5-FU. In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

No MeSH data available.


Related in: MedlinePlus

ACP1 mRNA and LMWPTP protein expression are increased in colorectal dysplasia and carcinoma as compared to non-dysplastic tissue(A, B) Using publicly available gene expression data from Affymetrix platforms, ACP1 expression (transcript 215227) was analyzed in carcinoma tissue (CRC) and adjacent normal colon tissue. Significantly higher expression of ACP1 mRNA expression was observed in carcinoma tissues (n = 17, P = 0.0005 by student's T-test). Gene expression array comparing ACP1 expression in colorectal adenoma to normal adjacent tissue shows increased ACP1 mRNA expression in cancer tissues (n = 32, P < 0.0001) (C). Tissues of patients with inactive ulcerative colitis (UC, n = 8), low grade dysplasia (n = 8), high grade dysplasia (HGD, n = 6), colorectal cancer (CRC, n = 12) and CRC liver metastasis (n = 5) were stained for LMWPTP by immunohistochemistry. Representative examples (10x and 40x magnifications) of UC, LGD, HGD, CRC and liver metastasis are shown. (D, E) LMWPTP staining was scored for percentage of positive intestinal epithelial cells as well as intensity of staining and statistical analysis was performed using Mann-Whitney t-test. (*P > 0.05; ** P > 0.01, *** P > 0.001).
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Figure 1: ACP1 mRNA and LMWPTP protein expression are increased in colorectal dysplasia and carcinoma as compared to non-dysplastic tissue(A, B) Using publicly available gene expression data from Affymetrix platforms, ACP1 expression (transcript 215227) was analyzed in carcinoma tissue (CRC) and adjacent normal colon tissue. Significantly higher expression of ACP1 mRNA expression was observed in carcinoma tissues (n = 17, P = 0.0005 by student's T-test). Gene expression array comparing ACP1 expression in colorectal adenoma to normal adjacent tissue shows increased ACP1 mRNA expression in cancer tissues (n = 32, P < 0.0001) (C). Tissues of patients with inactive ulcerative colitis (UC, n = 8), low grade dysplasia (n = 8), high grade dysplasia (HGD, n = 6), colorectal cancer (CRC, n = 12) and CRC liver metastasis (n = 5) were stained for LMWPTP by immunohistochemistry. Representative examples (10x and 40x magnifications) of UC, LGD, HGD, CRC and liver metastasis are shown. (D, E) LMWPTP staining was scored for percentage of positive intestinal epithelial cells as well as intensity of staining and statistical analysis was performed using Mann-Whitney t-test. (*P > 0.05; ** P > 0.01, *** P > 0.001).

Mentions: To understand the role of LMWPTP in colorectal cancer, we first investigated the gene expression levels of ACP1 using publicly available microarray datasets from Affymetrix Platforms. Expression of the LMWPTP encoding gene ACP1 (transcript 215227) was compared between CRC and normal adjacent colonic tissue (n = 17), and found to be significantly increased in the carcinoma group (P = 0.0005, Figure 1A). Colon cancer follows the adenoma to carcinoma sequence, and most cancers arise from dysplastic adenomas. Therefore, we also examined ACP1 expression levels in adenoma samples and again observed an increased mRNA expression in these samples (n = 32) compared to their normal adjacent colon tissue (P < 0.0001, Figure 1B).


Low molecular weight protein tyrosine phosphatase (LMWPTP) upregulation mediates malignant potential in colorectal cancer.

Hoekstra E, Kodach LL, Das AM, Ruela-de-Sousa RR, Ferreira CV, Hardwick JC, van der Woude CJ, Peppelenbosch MP, Ten Hagen TL, Fuhler GM - Oncotarget (2015)

ACP1 mRNA and LMWPTP protein expression are increased in colorectal dysplasia and carcinoma as compared to non-dysplastic tissue(A, B) Using publicly available gene expression data from Affymetrix platforms, ACP1 expression (transcript 215227) was analyzed in carcinoma tissue (CRC) and adjacent normal colon tissue. Significantly higher expression of ACP1 mRNA expression was observed in carcinoma tissues (n = 17, P = 0.0005 by student's T-test). Gene expression array comparing ACP1 expression in colorectal adenoma to normal adjacent tissue shows increased ACP1 mRNA expression in cancer tissues (n = 32, P < 0.0001) (C). Tissues of patients with inactive ulcerative colitis (UC, n = 8), low grade dysplasia (n = 8), high grade dysplasia (HGD, n = 6), colorectal cancer (CRC, n = 12) and CRC liver metastasis (n = 5) were stained for LMWPTP by immunohistochemistry. Representative examples (10x and 40x magnifications) of UC, LGD, HGD, CRC and liver metastasis are shown. (D, E) LMWPTP staining was scored for percentage of positive intestinal epithelial cells as well as intensity of staining and statistical analysis was performed using Mann-Whitney t-test. (*P > 0.05; ** P > 0.01, *** P > 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480753&req=5

Figure 1: ACP1 mRNA and LMWPTP protein expression are increased in colorectal dysplasia and carcinoma as compared to non-dysplastic tissue(A, B) Using publicly available gene expression data from Affymetrix platforms, ACP1 expression (transcript 215227) was analyzed in carcinoma tissue (CRC) and adjacent normal colon tissue. Significantly higher expression of ACP1 mRNA expression was observed in carcinoma tissues (n = 17, P = 0.0005 by student's T-test). Gene expression array comparing ACP1 expression in colorectal adenoma to normal adjacent tissue shows increased ACP1 mRNA expression in cancer tissues (n = 32, P < 0.0001) (C). Tissues of patients with inactive ulcerative colitis (UC, n = 8), low grade dysplasia (n = 8), high grade dysplasia (HGD, n = 6), colorectal cancer (CRC, n = 12) and CRC liver metastasis (n = 5) were stained for LMWPTP by immunohistochemistry. Representative examples (10x and 40x magnifications) of UC, LGD, HGD, CRC and liver metastasis are shown. (D, E) LMWPTP staining was scored for percentage of positive intestinal epithelial cells as well as intensity of staining and statistical analysis was performed using Mann-Whitney t-test. (*P > 0.05; ** P > 0.01, *** P > 0.001).
Mentions: To understand the role of LMWPTP in colorectal cancer, we first investigated the gene expression levels of ACP1 using publicly available microarray datasets from Affymetrix Platforms. Expression of the LMWPTP encoding gene ACP1 (transcript 215227) was compared between CRC and normal adjacent colonic tissue (n = 17), and found to be significantly increased in the carcinoma group (P = 0.0005, Figure 1A). Colon cancer follows the adenoma to carcinoma sequence, and most cancers arise from dysplastic adenomas. Therefore, we also examined ACP1 expression levels in adenoma samples and again observed an increased mRNA expression in these samples (n = 32) compared to their normal adjacent colon tissue (P < 0.0001, Figure 1B).

Bottom Line: In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia.Chemical inhibition of LMWPTP significantly reduces CRC growth.In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's Gravendijkwa, Rotterdam, The Netherlands.

ABSTRACT
Phosphatases have long been regarded as tumor suppressors, however there is emerging evidence for a tumor initiating role for some phosphatases in several forms of cancer. Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP; acid phosphatase 1 [ACP1]) is an 18 kDa enzyme that influences the phosphorylation of signaling pathway mediators involved in cancer and is thus postulated to be a tumor-promoting enzyme, but neither unequivocal clinical evidence nor convincing mechanistic actions for a role of LMWPTP have been identified. In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia. Chemical inhibition of LMWPTP significantly reduces CRC growth. Furthermore, downregulation of LMWPTP in CRC leads to a reduced migration ability in both 2D- and 3D-migration assays, and sensitizes tumor cells to the chemotherapeutic agent 5-FU. In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

No MeSH data available.


Related in: MedlinePlus